The invention relates to peritoneal dialysis fluids, and methods of making and using them. More particularly, it relates to the methods for preventing and treating complications due to peritoneal dialysis.
Peritoneal dialysis can be used to treat patients having chronic renal failure. In this procedure, peritoneal dialysis fluid is introduced into the peritoneal cavity of a subject. The fluid generally has a high glucose level, often in the 100 mM range. Introduction of this relatively high molarity fluid into the peritoneum causes the osmotic extraction of toxins, for example, urea creatinine, and other substances normally removed by the kidney, from the blood. It can also reduce the level of fluid in the patient.
The invention is based, in part, on the discovery that the use of peritoneal dialysis fluid, especially prolonged use, can result in decreasing permeability between the peritoneal dialysis fluid and the blood compartment, that high levels of glucose are involved in changes in the cells lining the peritoneum, that the high glucose levels activate PKC, and that the inhibition of PKC can prevent this chronic complication. The invention can treat an undesirable decrease in the efficiency of exchange between the peritoneal dialysis fluid and the vascular compartment.
Accordingly, the invention features, a method of treating a subject. The method includes:
introducing peritoneal dialysis fluid into the peritoneum of the subject; and
inhibiting a PKC in the subject,
thereby treating said subject.
In a preferred embodiment, an inhibitor of PKC is included in the peritoneal dialysis fluid. The inhibitor is preferably a specific inhibitor of PKC. The inhibitor can be an inhibitor of a PKC J, e.g., J1 or J2, K, L, or other isoform. The inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC J inhibitor LY333531, which is described in Ishi et al. (1996) Science 272:728-731, hereby incorporated by reference. LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nM.
In a preferred embodiment, the concentration of glucose in the peritoneal dialysis fluid is 200 nM.
Peritoneal dialysis fluid of the invention is particularly useful for subjects who are already peritoneal dialysis patients. In preferred embodiments, the subject has been a peritoneal dialysis patient for at least 2, 4, 6, 12, or 24 months, e.g., the subject has been administered peritoneal dialysis fluid, either one with or without a PKC inhibitor, periodically for at least 2, 4, 6, 12, or 24 months, or it has been at least 2, 4, 6, 12, or 24 months since the subjects first peritoneal dialysis administration. Peritoneal dialysis fluid of the invention can be administered to patients who have already developed permeability disjunction.
In other embodiments peritoneal dialysis fluid of the invention is useful for subjects who have not yet had peritoneal dialysis. Peritoneal dialysis fluid of the invention can be administered to patients who have not yet developed permeability disjunction.
In another aspect, the invention features, a method of treating a subject. The method includes:
introducing peritoneal dialysis fluid and an inhibitor of a PKC into the subject,
thereby treating the subject.
In a preferred embodiment, the peritoneal dialysis fluid and PKC inhibitor are co-administered to the subject; the peritoneal dialysis fluid and PKC inhibitor are introduced separately into the subject; the peritoneal dialysis fluid and PKC inhibitor are combined prior to introduction into the subject and administered together.
In a preferred embodiment, an inhibitor of PKC is included in the peritoneal dialysis fluid. The inhibitor is preferably a specific inhibitor of PKC. The inhibitor can be an inhibitor of a PKC xcex2, e.g., xcex21 or xcex22, xcex3, xcex4, or other isoform, or combinations thereof. The inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC xcex2 inhibitor LY333531. LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nM.
In a preferred embodiment, the concentration of glucose in the peritoneal dialysis fluid is 200 nM.
In a preferred embodiment, the subject is administered a second, third, fourth, or fifth, infusion of peritoneal dialysis fluid.
Peritoneal dialysis fluid of the invention is particularly useful for subjects who are already peritoneal dialysis patients. In preferred embodiments the subject has been a peritoneal dialysis patient for at least 2, 4, 6, 12, or 24 months, e.g., the subject has been administered peritoneal dialysis fluid, either one with or without a PKC inhibitor, periodically for at least 2, 4, 6, 12, or 24 months, or it has been at least 2, 4, 6, 12, or 24 months since the subjects first peritoneal dialysis administration. Peritoneal dialysis fluid of the invention can be administered to patients which have already developed permeability disjunction.
In other embodiments, peritoneal dialysis fluid of the invention is useful for subjects who have not yet had peritoneal dialysis. Peritoneal dialysis fluid of the invention can be administered to patients which have not yet developed permeability disjunction.
In a preferred embodiment, the subject is at risk for renal failure, for example, the subject is a patient in end-stage renal failure.
In another aspect, the invention features, a peritoneal dialysis fluid which includes an inhibitor of a PKC.
In a preferred embodiment, the peritoneal dialysis fluid is one described herein.
In a preferred embodiment, an inhibitor of PKC is included in the peritoneal dialysis fluid. The inhibitor is preferably a specific inhibitor of PKC. The inhibitor can be an inhibitor of a PKC xcex2, e.g., xcex21 or xcex22, xcex3, xcex4, or other isoform, or combinations thereof. The inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC xcex2 inhibitor LY333531. LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nM.
In a preferred embodiment, the concentration of glucose in the peritoneal dialysis fluid is 200 nM.
In yet another aspect, the invention features, a method of making an improved peritoneal dialysis fluid. The method includes, providing a peritoneal dialysis fluid and adding to that fluid an inhibitor of a PKC, for example an inhibitor described herein, for example LY333531.
In a preferred embodiment, an inhibitor of PKC is included in the peritoneal dialysis fluid. The inhibitor is preferably a specific inhibitor of PKC. The inhibitor can be an inhibitor of a PKC xcex2, e.g., xcex21 or xcex22, xcex3, xcex4, or other isoform, or combinations thereof. The inhibitor can be, for example, a bis (indolyl) maleimide, for example, the PKC xcex2 inhibitor LY333531. LY333531 can be present in the dialysis fluid at about 1-1,000, 5-750, 20-500, but more preferably 50-500 nM.
In a preferred embodiment, the concentration of glucose in the peritoneal dialysis fluid is 200 nM.
Subject, as used herein, can refer to a human subject, or a non-human animal, for example, a horse, cow, goat, pig, sheep or other veterinary, food or fiber producing animal, in need of dialysis. The subject can be an individual at risk for (e.g., the individual can have or be predisposed to have) end-stage renal disease, from any cause.
Other features and advantages of the invention will be apparent from the description herein and from the claims.